14: Group Sequential Design for Covariate-adjusted Restricted Mean Survival Time Comparisons

Thomas M. Menino Convention & Exhibition Center 

The restricted mean survival time (RMST), defined as the mean event-free survival time within a prespecified horizon [0, tau], provides an interpretable estimand for comparing event times that remains valid under nonproportional hazards. Group sequential (GS) designs enable early stopping for efficacy and futility, while covariate adjustment can improve efficiency when baseline prognostic factors are available. We develop a covariate-adjusted GS testing framework for comparing RMSTs in randomized trials. RMST estimation is conducted by a generalized linear model fitted using inverse probability of censoring weighted estimating equations, allowing efficient adjustment without assuming proportional hazards. The covariate-adjusted GS test statistics are shown to possess an independent increments covariance structure asymptotically, permitting the use of standard methods to control the overall type I error rate. Simulation studies across various choices of link functions, censoring patterns and sample sizes show that good type I error control and nominal power levels are achieved. An application to the BMT CTN 1101 trial illustrates the proposed methodology in a real-world setting.

Restricted mean survival time (RMST)

Group sequential design

Covariate adjustment

Independent increments

Blood and marrow transplantation

Inverse probability of censoring weighting 

Biopharmaceutical Section